Viral Link to Chronic Fatigue Chronic fatigue syndrome (CFS) is a complex and debilitating disorder that is often linked to immune system dysfunction but whose cause(s) remain mysterious. Lombardi et al. (p. 585 , published online 8 October; see the Perspective by Coffin and Stoye ) now present a tantalizing new lead. In blood samples from 101 patients with well-documented CFS, over two-thirds (68) contained DNA from a recently described human gammaretrovirus, xenotropic murine leukemia virus–related virus (XMRV), which possesses sequence similarity to a murine leukemia virus. Cell culture assays confirmed that XMRV derived from CFS patient plasma and from T and B lymphocytes was infectious. Although the correlation with CFS is striking, whether the virus plays a causal role in the disorder remains to be determined. Interestingly, nearly 4% of the 218 healthy donors tested were positive for XMRV, which suggests that this virus—whose pathogenic potential is unknown—may be present in a significant proportion of the general population.
Cas NS-1 is an acutely transforming murine retrovirus that induces pre-B and pro-B cell lymphomas. Molecular cloning showed it was generated from the ecotropic Cas-Br-M virus by sequential recombinations with endogenous retroviral sequences and a cellular oncogene. The oncogene sequence shows no homology with known oncogenes but some similarity to the yeast transcriptional activator GCN4. A 100-kDa gag-cbl fusion protein, with no detectable kinase activity, is responsible for the cellular transformation. The cellular homologue of v-cbl, present in mouse and human DNA, is expressed in a range of hemopoietic lineages.The ability of retroviruses to recombine with host chromosomal DNA has enabled the identification of genes with cancer-causing potential, collectively known as oncogenes (for reviews, see refs. 1-3). From studies of avian and mammalian retroviruses numerous oncogenes have been isolated and this has led to dramatic progress in the definition and understanding of the molecular basis of cancer. We have been examining the tumors that develop in mice after infection with an ecotropic retrovirus called Cas-Br-M. This virus was originally isolated from a wild mouse of the Lake Casitas region of California (4) and induces T-and B-cell lymphomas, erythroleukemia, and myeloid leukemia with latent periods of 5-8 months (5). It remains unclear whether Cas-Br-M generates this range of tumors by infecting multipotential hemopoietic cells or by infecting cells committed to a lineage. Furthermore, the etiological agent in some of these tumors is a recombinant virus formed soon after inoculation (6). This class of murine retrovirus is termed mink cell focus-forming (MCF) virus and evolves by recombination between the infecting ecotropic virus and nonecotropic retroviral sequences present in the mouse genome (7,8).To determine the relative importance of Cas-Br-M and MCF viruses in the induction of hemopoietic neoplasms, cell-free extracts were prepared from a range of tumors arising in NFS/N mice inoculated at birth with Cas-Br-M (6). These extracts were inoculated into newborn NFS/N mice since it was reasoned if Cas-Br-M was the tumor-inducing virus, then each extract should produce a range of tumor phenotypes with a long latent period. Alternatively, if lineage-specific MCF viruses in the extracts were the dominant tumor-inducing agents, then the tumors should correspond to the primary tumor and the latency should be reduced. The results from 3 of 12 extracts tested were consistent with the latter possibility (6).One of the three extracts producing a high proportion of tumors with the same phenotype as the primary tumor and a reduced latency was called Cas NS-1. This extract was prepared from the spleen of a mouse with a pre-B cell lymphoma that developed 28 weeks after Cas-Br-M infection. Injection of the Cas NS-1 extract into newborn NFS/N mice resulted in a high proportion of pre-B cell lymphomas with a mean latent period of 16 weeks. This result indicated that a tumorigenic virus with a lineage preference...
C57BL/6 mice infected with a mixture of murine leukemia viruses (MuLV) develop a syndrome characterized by lymphoproliferation and profound immunodeficiency. Analyses of this viral mixture (LP-BM5 MuLV) showed that it includes replication-competent ecotropic and mink cell focus-inducing MuLV and defective viruses with genome sizes of 3.8-6.5 kilobases. The ecotropic and mink cell focus-inducing MuLV biologically cloned from the mixture did not induce disease, whereas viral preparations containing the ecotropic MuLV and 4.8-kilobase defective virus were active. Cells producing the 4.8-kilobase defective virus expressed an unusual gag-encoded polyprotein of Mr 60,000.
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